The relative analgesic potency of 11 opioid agents was assessed by using the acetic acid test in amphibians. Systemic administration of the mu agonists, fentanyl, levorphanol, methadone, morphine, meperidine and codeine; the partial mu agonist, buprenorphine; and the kappa agonists nalorphine, bremazocine, U50488 and CI-977 was made by s.c. injection into the dorsal lymph sac of the Northern grass frog, Rana pipiens. All agents produced a dose-dependent and long-lasting analgesia which persisted for at least 4 hr. The analgesic effects of single doses of each agent were significantly blocked or reduced by pretreatment with naltrexone. Systemic opioids produced log dose-response curves which yielded ED50 values ranging from 1.4 nmol/g for fentanyl to 320.9 nmol/g for nalorphine. Comparison of ED50 values gave a rank order of analgesic potency = fentanyl > CI-977 > levorphanol > U50488 > methadone > bremazocine > morphine > buprenorphine > meperidine > codeine > nalorphine. The relative analgesic potency of mu opioids in amphibians was significantly correlated with relative analgesic potency of these same agents obtained on the mouse writhing and hot plate tests. These data suggest that the amphibian model may serve as an adjunct or alternative model for the testing of opioid agents. Furthermore, given the inactivity of kappa opioids on rodent hot plate and tail-flick tests, the acetic acid test in amphibians may be especially well-suited for the assessment of opioid analgesia after administration of kappa-selective opioids.
"Early work in our lab demonstrated that opioid receptors mediate antinociceptive effects in non-mammalian species. Specifically, the antinociceptive potency of mu-, delta-, and kappaselective opioid agonists after systemic (Stevens et al., 1994), intraspinal (Stevens, 1996), or intracerebroventricular (Stevens and Rothe, 1997) administration in amphibians was highly correlated to that observed in mammals and to the relative potency of opioid analgesics in human clinical studies. These results, and other studies over the last two decades, validated the amphibian model as an alternative or adjunct model for pain and analgesia research (Stevens, 2008). "
[Show abstract][Hide abstract] ABSTRACT: This study presents a direct comparison of the ligand binding and signaling profiles of a mammalian and non-mammalian mu opioid receptor. Opioid ligand binding and agonist potencies were determined for an amphibian (Rana pipiens) mu opioid receptor (rpMOR) and the human mu opioid receptor (hMOR) in transfected, intact Chinese hamster ovary (CHO) cells. Identical conditions were employed such that statistically meaningful differences between the two receptors could be determined. Identifying these differences is an important first step in understanding how evolutionary changes affect ligand binding and signaling in vertebrate opioid receptors. As expected, the rank of opioid ligand affinity for rpMOR and hMOR was consistent with the ligands' previously characterized type-selectivity. However, most of the opioid ligands tested had significant differences in affinity for rpMOR and hMOR. For example, the mu-selective agonist, DAMGO ([d-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin), had a 10.9-fold greater affinity (K(i)) for hMOR (K(i)=268 nM) than rpMOR (K(i)=2914 nM). In addition, differences in signaling between these receptors were found by measuring inhibition of cAMP accumulation by morphine or DAMGO. DAMGO was significantly more potent (13.6-fold) in CHO cells expressing hMOR versus those expressing rpMOR. In addition, a significantly greater maximal inhibition was elicited by both opioid agonists in cells expressing hMOR. In summary, this study supports an ongoing effort to better understand how vertebrate evolution has shaped opioid receptor properties and function.
European Journal of Pharmacology 11/2008; 599(1-3):36-43. DOI:10.1016/j.ejphar.2008.09.043 · 2.53 Impact Factor
"For opioid antagonism experiments, systemic naltrexone (100 nmol/g) or saline was administered 1h before the spinal administration of agonists. Systemic administration was made by bolus injection into the dorsal lymph sac at a volume of 10 μl/g body weight (Stevens et al., 1994). Treatment groups consisted of six to eight animals per dose. "
[Show abstract][Hide abstract] ABSTRACT: Nociceptin, also known as orphanin FQ, is a opioid-like neuropeptide that mediates its effects at the nociceptin receptor, a member of the G protein-coupled receptor superfamily. In mammals, nociceptin produces analgesia after spinal administration, however the role of nociceptin and nociceptin receptors in the modulation of noxious stimuli in non-mammalian species has not been examined. In an amphibian pain model using the acetic acid test with Rana pipiens, nociceptin and nociceptin1-13 amide produced dose-dependent antinociception (1-100 nmol), blocked by the nociceptin antagonist, [Nphe1]-nociceptin1-13 amide (30 nmol), but not the opioid antagonist, naltrexone (100 nmol/g, s.c.). Conversely, the antinociceptive effects of micro, delta, and kappa opioid receptor agonists were not blocked by the nociceptin antagonist. Nociceptin and nociceptin1-13 amide were the least potent of the opioid agonists tested. These studies demonstrate that spinal nociceptin receptors and not opioid receptors mediate the antinociceptive effect of nociceptin. Considered with previous findings, these behavioral data supports a role for nociceptin inhibition of spinal nociception in amphibians and perhaps all vertebrates.
"The strategy here is therefore to use a l-opioid receptor agonist that has both high potency as well as high intrinsic opioid agonist activity at least as great as that of methadone. The clinically available fentanyl analogues generally satisfy these criteria (Adams et al., 1990; Barrett et al., 2003; Stevens et al., 1994). Remifentanil, a l-opioid receptor agonist (James et al., 1991) with a rapid onset/offset of action, is metabolised by non-specific esterases (Westmoreland et al., 1993). "
[Show abstract][Hide abstract] ABSTRACT: The treatment of acute pain in patients maintained on methadone is difficult due to increased pain sensitivity (hyperalgesia) and cross-tolerance to other opioids. This study aimed to investigate whether remifentanil elicits antinociception in methadone-maintained subjects in a dose-dependent manner. Eight chronic methadone-maintained subjects attended the testing session approximately 20 h after their normal methadone dose (range 50-110 mgday(-1)). Following a 20 min saline infusion, subjects were administered intravenous remifentanil in seven increasing doses ranging from 0.5 to 3.5 microgkg(-1)min(-1), each for 2 0min. Testing was performed in the last 10 min of each infusion. The testing measures included nociception, as measured by the cold pressor test, withdrawal using the subjective opiate withdrawal scale (SOWS), and subjective opioid effects using the morphine-benzedrine group scale (MBG). Results showed dose-dependent increase in cold pressor tolerance time from baseline of 15.6+/-3.5 (mean+/-SEM)s up to 77.3+/-24.7s during this dosing protocol. During the infusion typical mu-opioid receptor agonist side effects were observed, but with no withdrawal. Methadone-maintained patients demonstrate significant tolerance to remifentanil and may require opioid doses 20-30 higher than required for the treatment of acute pain in opioid-naïve patients.
European journal of pain (London, England) 03/2008; 12(7):926-33. DOI:10.1016/j.ejpain.2007.12.012 · 2.93 Impact Factor
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